title: DCLK1 marks a morphologically distinct subpopulation of cells with stem cell properties in preinvasive pancreatic cancer.
abstract: OBJECTIVE
  As in other tumor types, progression of pancreatic cancer may require a functionally unique population of cancer stem cells. Although such cells have been identified in many invasive cancers, it is not clear whether they emerge during early or late stages of tumorigenesis. Using mouse models and human pancreatic cancer cell lines, we investigated whether preinvasive pancreatic neoplasia contains a subpopulation of cells with distinct morphologies and cancer stem cell-like properties.
  
  
  METHODS
  Pancreatic tissue samples were collected from the KC(Pdx1), KPC(Pdx1), and KC(iMist1) mouse models of pancreatic intraepithelial neoplasia (PanIN) and analyzed by confocal and electron microscopy, lineage tracing, and fluorescence-activated cell sorting. Subpopulations of human pancreatic ductal adenocarcinoma (PDAC) cells were similarly analyzed and also used in complementary DNA microarray analyses.
  
  
  RESULTS
  The microtubule regulator DCLK1 marked a morphologically distinct and functionally unique population of pancreatic cancer-initiating cells. These cells displayed morphological and molecular features of gastrointestinal tuft cells. Cells that expressed DCLK1 also expressed high levels of ATAT1, HES1, HEY1, IGF1R, and ABL1, and manipulation of these pathways in PDAC cell lines inhibited their clonogenic potential. Pharmacological inhibition of γ-secretase activity reduced the abundance of these cells in murine PanIN in a manner that correlated with inhibition of PanIN progression.
  
  
  CONCLUSIONS
  Human PDAC cells and pancreatic neoplasms in mice contain morphologically and functionally distinct subpopulations that have cancer stem cell-like properties. These populations can be identified at the earliest stages of pancreatic tumorigenesis and provide new cellular and molecular targets for pancreatic cancer treatment and/or chemoprevention.
authors.affiliation: Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland; The McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Bailey
authors.affiliation: Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Janivette
authors.initials: J
authors.lastname: Alsina
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Zeshaan A
authors.initials: ZA
authors.lastname: Rasheed
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Florencia M
authors.initials: FM
authors.lastname: McAllister
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Ya-Yuan
authors.initials: YY
authors.lastname: Fu
authors.affiliation: Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts; Department of Internal Medicine, Medical University Hospital, Tuebingen, Germany.
authors.forename: Ruben
authors.initials: R
authors.lastname: Plentz
authors.affiliation: Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
authors.forename: Hao
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Pankaj J
authors.initials: PJ
authors.lastname: Pasricha
authors.affiliation: Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Nabeel
authors.initials: N
authors.lastname: Bardeesy
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: William
authors.initials: W
authors.lastname: Matsui
authors.affiliation: Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Anirban
authors.initials: A
authors.lastname: Maitra
authors.affiliation: Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland; The McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address: stleach@jhmi.edu.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Leach
mesh_terms: D000818:Animals; D002278:Carcinoma in Situ / Q000378:metabolism* / Q000473:pathology; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism* / Q000473:pathology; D002471:Cell Transformation, Neoplastic; D004195:Disease Models, Animal; D000089742:Doublecortin-Like Kinases; D005434:Flow Cytometry; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D008854:Microscopy, Electron; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism* / Q000473:pathology
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C117347:DCLK1 protein, human; D000089742:Doublecortin-Like Kinases; C485525:Dclk1 protein, mouse; D017346:Protein Serine-Threonine Kinases
keywords: ADM; AcTub; Acetylated Tubulin; Dclk1; FACS; GFP; Kras; Notch; PDAC; PanIN; TEM; acetylated α-tubulin; acinar-to-ductal metaplasia; doublecortin and Ca(2+)/calmodulin-dependent kinase-like 1; fluorescence-activated cell sorting; green fluorescent protein; mPanIN; murine pancreatic intraepithelial neoplasia; pancreatic ductal adenocarcinoma; pancreatic intraepithelial neoplasia; transmission electron microscopy